Differential effects of prazosin and rauwolsin on the release of prostaglandins I2 and E2 from the perfused mesenteric arterial bed of the rabbit following nerve stimulation

Sympathetic nerve stimulation of the perfused mesenteric arterial bed of the rabbit, , increase the secretion of prostaglandin (PG)I₂ and PGE₂. Prazosin (4.8 × 10⁻⁶), and α₁ adrenergic receptor antagonist, inhibited this inrease in release of PGI₂ but not of PGE₂ whereas rauwolsin (10⁻⁷ M), an α₂ adrenergic receptor antagonist, inhibited the increase in release of PGE₂ but not of PGI₂. Prazosin (10⁻⁶ M) completely blocked the vasoconstrictor response to nerve stimulation, and to norepinephrine and phenylephrine administration, suggesting there to be little of an α₂ adrenergic receptor component in this response. It is concluded that the increase in PGI₂ release follows the activation of α₁ adrenergic receptors and is therefore post-junctional in origin, whereas the increase in PGE₂ release follows the activation of α₂ adrenergic receptors and may be pre- and/or post-junctional in origin.Indomethacin (2.8 × 10⁻⁷, 5.6 × 10⁻⁷ and 1.12 × 10^{−6 M} did not affect the vasoconstrictor responses to nerve stimulation at 10 Hz, whereas rauwolsin (10⁻⁷ M) in the presence of indomethacin substantially increased them. These results indicate that PGE₂ does not regulate norepinephrine release following nerve stimulation at 10 Hz to rabbit mesenteric arteries, and that the inhibition of norepinephrine release following stimulation of α₂ pre-junctional receptors is independent of PG involvement.     

The effects of microsomal prostaglandin E synthase-1 deletion in acute cardiac ischemia in mice

The goal of the present study was to assess how genetic loss of microsomal prostaglandin E₂ synthase-1 (mPGES-1) affects acute cardiac ischemic damage after coronary occlusion in mice. Wild type (WT), heterozygous (mPGES-1^+/−), and homozygous (mPGES-1^−/−) knockout mice were subjected to left coronary artery occlusion. At 24 h, myocardial infarct (MI) volume was measured histologically. Post-MI survival, plasma levels of creatine phosphokinase (CPK) and cardiac troponin-I, together with MI size, were similar in WT, mPGES-1^+/− and mPGES-1^−/− mice. In contrast, post-MI survival was reduced in mPGES-1^−/− mice pretreated with I prostanoid receptor (IP) antagonist (12/16) compared with vehicle-treated controls (13/13 mPGES-1^−/−) together with increased CPK and cardiac troponin-I release. The deletion of mPGES-1 in mice results in increased prostacyclin I₂ (PGI₂) formation and marginal effects on the circulatory prostaglandin E₂ (PGE₂) level. We conclude that loss of mPGES-1 results in increased PGI₂ formation, and in contrast to inhibition of PGI₂, without worsening acute cardiac ischemic injury.     

Effects of prostacyclin on coronary circulation, heart rate and myocardial contractile force in isolated hearts of guinea PIG and rabbit — Comparison with prostaglandin E2

Infusions of prostacyclin (PGI₂) (3 × 10⁻¹⁰ − 3 × 10⁻⁷M) into the coronary circulation of isolated hearts from guinea pigs or rabbits resulted in a concentration-dependent decrease in the coronary perfusion pressure (CPP). There was a slight decrease in left ventricular systolic pressure in the heart of the rabbit, whereas the heart rate remained unchanged. PGE₂ was without effect on the heart of the rabbit but was as potent as PGI₂ in decreasing the CPP in the guinea pig heart. 6-oxo-PGF_1α (up to 3 × 10⁻⁶ M) did not affect any of the parameters measured.     

Regulations of macrophage-mediated tumor cell killing by prostaglandins: Comparison of the effects of PGE2 and PGI2

Mouse resident peritoneal macrophages stimulated by purified bacterial lipopolysaccharide (LPS) produced both prostaglandin E₂ (PGE₂) and prostaglandin I₂ (PGI₂), the latter detected as its stable metabolite, 6-keto PGF_1α. Maximum production, induced in each case by 1 ng/ml purified LPS, was in the range of 10⁻⁷M for PGI₂ and 3 × 10⁻⁸M for PGE₂. A quantitatively similar increase in intracellular levels of macrophage cyclic AMP (measured on a whole cell basis), with a similar duration of effect, was stimulated by PGE₂ and PGI₂; however, only PGE₂ had a negative regulatory effect on macrophage activation for tumor cell killing. These data confirm that more than a whole cell increase in the concentration of cyclic AMP is needed to shut off nonspecific tumor cell killing mediated by LPS-activated resident peritoneal macrophages.     

Actions of prostacyclin (PGI2) on adrenergic neuroeffector transmission in the rabbit kidney

In the Tyrode's perfused rabbit kidney PGI₂ (1.3 × 10⁻⁸-3.3 × 10^−7M) dose-dependently inhibited vasoconstrictor responses to sympathetic nerve stimulation, as did PGE₂. The dose-effect curve of the two compounds differed, making PGI₂ the less potent in the low concentration and the more potent in the high. PGI₂ also inhibited the vasoconstrictor response to exogenous noradrenaline, but it had no effect on transmitter release. The main metabolite of PGI₂, 6-keto-PGF_1α, was ineffective both on noradrenaline release and on vascular responses to nerve stimulation or exogenous noradrenaline. It is suggested that PGI₂,if a significant renal prostaglandin, may modulate renal neuroeffector transmission post-junctionally, thereby forming a complement to the prejunctional action of PGE₂.     

The mechanism of enhancement by fatty acid hydroperoxides of anaphylactic mediator release

Fragments of chopped lung from indomethacin treated guinea-pigs had an anti-aggregating effect when added to human platelet rich plasma (PRP), probably due to the production of prostacyclin (PGI₂) since the effect was inhibited by 15-hydroperoxy arachidonic acid (15-HPAA, 10 μg ml⁻¹). Both 15-HPAA (1–20 μg ml⁻¹ min⁻¹) and 13-hydroperoxy linoleic acid (13-HPLA, 20 μg ml⁻¹ min⁻¹) caused a marked enhancement of the anaphylactic release of histamine, slow-reacting substance of anaphylaxis (SRS-A) and rabbit aorta contracting substance (RCS) from guinea-pig isolated perfused lungs. This enhancement was not reversed by the concomitant infusion of either PGI₂ (5 μg ml⁻¹ min⁻¹) or 6-oxo-prostaglandin F_1α (6-oxo-PGF_1α, 5 μg ml⁻¹ min⁻¹). Anaphylactic release of histamine and SRS-A from guinea-pig perfused lungs was not inhibited by PGI₂ (10 ng - 10 μg ml⁻¹ min⁻¹) but was inhibited by PGE₂ (5 and 10 μg ml⁻¹ min⁻¹). Antiserum raised to 5,6-dihydro prostacyclin (PGI₁) in rabbits, which also binds PGI₂, had no effect on the release of anaphylactic mediators. The fatty acid hydroperoxides may enhance mediator release either indirectly by augmenting thromboxane production or by a direct effect on sensitized cells. Further experiments to distinguish between these alternatives are described in the accompanying paper (27).     

Prostaglandin I2 is less relaxant than prostaglandin E2 on the lamb ductus arteriosus

Prostaglandin(PG) I₂ and its stable metabolite, 6-keto-PGF_1α, were tested on the isolated ductus arteriosus from mature fetal lambs. PGI₂ relaxed the ductus in high doses (threshold 10⁻⁶M) and its activity disappeared on standing at room temperature for 30 minutes. 6-keto-PGF_1α was inactive at all doses. By contrast, PGE₂ produced a dose-dependent relaxation over a range between 10⁻¹⁰ and 10⁻⁶ M. These findings confirm that PGE₂ is the most potent ductal relaxant among the known derivatives of arachidonic acid. PGE₂ probably maintains ductus patency in the fetus and, together with PGE₁, remains the compound of choice in the management of newborns requiring a viable ductus for survival.     

Effect of PGI2, PGE2 and 6-keto PGF1α on canine gastric blood flow and acid secretion

Prostaglandins (PG)I₂, PGE₂ and 6-keto PGF₁α were infused directly into the gastric arterial supply at 10⁻⁹, 10⁻⁸ and 10⁻⁷ g/kg/min during an intra-gastric artery pentagastrin infusion in anesthetized dogs. 6-keto PGF₁α was also infused at 10⁻⁶ g/kg/min. Gastric arterial blood flow was measured continuously with a non-cannulating electromagnetic flow probe and gastric acid collected directly from the stomach. PGI₂ and PGE₂ produced similar dose-dependent increases in blood flow with an increase of more than four-fold at the highest dose. Both PGs inhibited acid output over this dose range with PGE₂ having 10 times the potency of PGI₂. 6-keto PGF₁α was at least 1000 times less active than PGI₂ or PGE₂ at increasing blood flow and failed to inhibit acid output even at 10⁻⁶ g/kg/min.     

Prostaglandins and renin release: II. Assessment of renin secretion following infusion of PGI2, E2 and D2 into the renal artery of anesthetized dogs

The influence of intra-renal infusions of prostaglandin (PG) I₂, PGE₂ and PGD₂ on renin secretion and renal blood flow was investigated in renally denervated, beta-adrenergic blocked, indomethacin treated dogs with unilateral nephrectomy. All three prostaglandins when infused at doses of 10⁻⁸ g/kg/min and 10⁻⁷ g/kg/min resulted in marked renal vasodilation. Renin secretory rates increased significantly with both PGI₂ and PGE₂ at the 10⁻⁸ g/kg/min and 10⁻⁷ g/kg/min infusion rates in a dose dependent manner. However, PGD₂ was inactive. At 10⁻⁷ g/kg/min, PGI₂ infusions resulted in systemic hypotension indicating recirculation of this prostaglandin. These findings suggest that PGI₂ should be included among the cyclooxygenase derived metabolites of arachidonic acid to be considered as possible mediators of renin release.     

Prostaglandin I2 as a potentiator of acute inflammation in rats.

Prostaglandin I2 potentiated the paw swelling induced by carrageenin in rats. Prostaglandin I2 (0.1 microgram) showed similar activity to PGE1 (0.01 microgram). This potentiating property disappeared in 60 minutes and was completely abolished by diphenhydramine (25 mg kg-1, i.p.). In vascular permeability tests, PGI2 itself (2.5 X 10(-10) mol, 88 ng) caused no dye leakage reaction, but PGE1 (2.5 X 10(-10) mol, 88.5 ng) caused a significant dye leakage. This effect of PGE1 was statistically significant compared with vehicle- or PGI2-treated groups (p less than 0.05). Prostaglandin I2 potentiated the increased vascular permeability induced by 5-hydroxytriptamine (2.5 X 10(-10) mol), bradykinin (5 X 10(-10) mol) and histamine (2 X 10(-10) to 2 X 10(-8) mol). The potentiation was the most evident in the case of histamine.     

Specific binding of a stable prostacyclin analogue (Iloprost) to rat oxyntic mucosa

It has been reported that prostacyclin (PGI₂) is the predominant species of prostanoid in rat oxyntic mucosa. However since PGI₂ is inactivated under physiological conditions it has not been possible to demonstrate specific PGI₂ binding to the rat stomach. Therefore a stable PGI₂ analogue, Iloprost, was chosen as ligand in this study. Binding of labelled Iloprost to the 20,000 xg homogenate fraction of rat oxyntic mucosa was specific, dissociable, saturable and dependent upon the temperature and time of incubation. Neither tritiated PGE₂ nor 6 keto PGF_1α displayed any significant specific binding to rat stomach. A Scatchard plot of the equilibrium binding data for Iloprost was curvilinear and could be resolved into at least two binding sites. The average parameters determined from Scatchard analysis were: dissociation constants of 1.8 × 10⁻¹¹ M and 7.1 × 10⁻⁸ M and corresponding binding site concentrations of 12.0 pmole/mg and 4800 pmoles/mg protein respectively. PGI₂ was less potent than unlabelled Iloprost in displacing ³H-Iloprost from its binding site. The addition of PGE₂ to the incubation medium resulted in an increase in ³H-Iloprost binding. It is concluded that rat oxyntic mucosa has specific binding sites for PGI₂-like agents but not for either PGE₂ or 6 keto PGF_1α.     

The in vitro effect of indomethacin on basal bone resorption, on prostaglandin production and on the response to added prostaglandins

Mouse calvaria were maintained in organ culture without serum additives. Basal active resorption, as measured by ⁴⁵Ca and hydroxyproline release, was significantly inhibited to 74% control levels by indomethacin (1.4 × 10⁻⁷ M). Prostaglandin F and prostaglandin E₂ production, determined by radioimmunoassay, were both significantly lowered by this concentration of indomethacin. DNA, protein and hydroxyproline synthesis, as indices of cell toxicity, were unaffected by low concentrations of indomethacin, while concentrations of 1.4 × 10⁻⁶M inhibited protein synthesis (p<0.005). In the presence of indomethacin (1.4 × 10⁻⁷M) both PGE₂ and PGF_2α stimulated resorption in a dose-dependent manner, with PGE₂ being the more potent. Neither prostaglandin affected hydroxyproline synthesis at low concentrations, but PGE₂ had a marked inhibitory action at a higher concentration (10⁻⁶M). In combination, the effects of PGE₂ and PGF_2α showed no evidence of synergism or any antagonistic action. The study shows that in vitro calcium and hydroxyproline resorption in the unstimulated mouse calvaria are inhibited by indomethacin at concentrations measured in serum during human therapy. The decreased PGF and PGE₂ production associated with this decreased bone resorption in the presence of non-toxic concentrations of indomethacin would suggest a role for these prostaglandins in maintaining the basal resorption of cultured bone.     

Enhancement of leukotriene D4-induced contraction of guinea-pig isolated trachea by platelet activating factor

The effect of platelet activating factor (PAF), a potent lipid mediator of inflammation, was examined in the induction of airway hyperreactivity to known mediators of anaphylaxis. Concentration-dependent contractions of the isolated guinea-pig trachea to PAF (10⁻⁷ − 10⁻⁵M) were produced and an EC₅₀ value was found to be 7.5 × 10⁻⁷M. Pretreatment for 30 min with a known PAF inhibitor, CV-3988 (10⁻⁵ or 10⁻⁴M), produced significant inhibition of PAF contractions; however, at 10⁻⁶M, CV-3988 had no effect. In the presence of meclofenamic acid (10⁻⁶M), the concentration-response curve to PAF was shifted significantly upward and to the left. This potentiation could be reversed by pretreating the tissues with the peptidoleukotriene antagonists, FPL 55712 or SK&F 102922 (10⁻⁵M). Pretreatment with PAF concentrations having essentially no intrinsic activity (10⁻⁸, 10⁻⁷) significantly enhanced the contraction of guinea-pig trachea to various concentrations of LTD₄ and to certain concentrations of a thromboxane mimic (U-46619). Pretreatment with lyso-PAF failed to potentiate the LTD₄ response, while pretreatment with CV-3988 reverse the potentiation by PAF of the lower concentrations of LTD₄. However, PAF failed to enhance contractions (with or without the presence of meclofenamic acid) to acetylcholine, histamine, PGD₂ or LTC₄ (in the presence of serine borate). These results indicate a possible role for PAF as a mediator of airway hyperreactivity.     

Stimulation by prostaglandin E2 of glucagon and insulin release from isolated rat pancreas

To ascertain whether prostaglandins (PG) may play a role in the secretion of glucagon and in an attempt to elucidate the conflicting observations on the effects of PG on insulin release, the isolated intact rat pancreas was perfused with solutions containing 1.1 × 10⁻⁹ to 1.8 × 10⁻⁵M PGE₂. In the presence of 5.6 mM glucose significant increments in portal venous effluent levels of glucagon and insulin were observed in response to minimal concentrations of 2.8 × 10⁻⁸ and 1.4 × 10⁻⁷M PGE₂, respectively; a dose-response relationship was evident for both hormones at higher concentrations of PGE₂. When administered over 60 seconds, 1.4 × 10⁻⁶M PGE₂ resulted in a significant increase in glucagon levels within 24 seconds and in insulin within 48 seconds. Ten-minute perfusions of 1.4 × 10⁻⁶M PGE₂ elicited biphasic release of both islet hormones; Phase I glucagon release preceded that of insulin. Both phases of the biphasic glucagon and insulin release which occurred in response to 15-minute perfusions of 10 mM arginine were augmented by PGE₂. These observations indicate that PGE₂ can evoke glucagon and insulin release at concentrations close to those observed by others in the extracts of rat pancreas. We conclude that PG may be involved in the regulation of secretion of glucagon and insulin and may mediate and/or modify the pancreatic islet hormone response to other secretagogues.     

Laccase-catalyzed oxidation of phenolic compounds in organic media

Rhus vernificera laccase-catalyzed oxidation of phenolic compounds, i.e., (+)-catechin, (−)-epicatechin and catechol, was carried out in selected organic solvents to search for the favorable reaction medium. The investigation on reaction parameters showed that optimal laccase activity was obtained in hexane at 30 °C, pH 7.75 for the oxidation of (+)-catechin as well as for (−)-epicatechin, and in toluene at 35 °C, pH 7.25 for the oxidation of catechol. E_a and Q₁₀ values of the biocatalysis in the reaction media of the larger log p solvents like isooctane and hexane were relatively higher than those in the reaction media of lower log p solvents like toluene and dichloromethane. Maximum laccase activity in the organic media was found with 6.5% of buffer as co-solvent. A wider range of 0–28 μg protein/ml in hexane than that of 0–16.7 μg protein/ml in aqueous medium was observed for the linear increasing conversion of (+)-catechin. The kinetic studies revealed that in the presence of isooctane, hexane, toluene and dichloromethane, the K_m values were 0.77, 0.97, 0.53 and 2.9 mmol/L for the substrate of (+)-catechin; 0.43, 0.34, 0.14 and 3.4 mmol/L for (−)-epicatechin; 2.9, 1.8, 0.61 and 1.1 mmol/L for catechol, respectively, while the corresponding V_max values were 2.1 × 10⁻², 2.3 × 10⁻², 0.65 × 10⁻² and 0.71 × 10⁻² δA/μg protein min); 1.8 × 10⁻², 0.88 × 10⁻², 0.19 × 10⁻² and 1.0 × 10⁻² δA/μg protein min); 0.48 × 10⁻², 0.59 × 10⁻², 0.67 × 10⁻² and 0.54 × 10⁻² δA/μg protein min), respectively. FT-IR indicated the formation of probable dimer from (+)-catechin in organic solvent. These results suggest that this laccase has higher catalytic oxidation capacity of phenolic compounds in suitable organic media and favorite oligomers could be obtained.     

Bottlenecks to water transport in Quercus robur L.: the abscission zone and its physiological consequences

Cladoptosis, the abscission of twigs, is the main mechanism of changes in crown structure in senescing pedunculate oak (Quercus robur L.). We tested the hypotheses that abscission zones in nodes of old pedunculate oak trees reduce leaf-specific hydraulic conductance of shoots and thereby limit the stomatal conductance and assimilation.Hydraulic conductance and leaf-specific hydraulic conductance, measured with a high pressure flowmeter in 0.5–1.5 m long shoots, were significantly lower in shoots of low vigour compared to vigorous growing shoots in a 165-years-old stand in the southeast of Germany. Two types of bottlenecks to water transport could be identified in shoots of old oak trees, namely nodes and abscission zones. In young twigs, vessel diameter and vessel density in nodes with abscission zones were significantly reduced compared with internodes. In nodes without abscission zones, vessel density was significantly reduced. The reduction of hydraulic conductance was especially severe in the smallest and youngest shoots with diameters less than 2 mm. Internodes of 1–5 mm sapwood diameter had an average hydraulic conductance of 7.13×10⁻⁶±0.2×10⁻⁶ kg s⁻¹ m⁻¹ MPa⁻¹, compared to 4.54×10⁻⁶±0.3×10⁻⁶ kg s⁻¹ m⁻¹ MPa⁻¹ in those with nodes.Maximum stomatal conductance and maximum net assimilation rate increased significantly with hydraulic conductance and leaf-specific hydraulic conductance. Maximum rate of net photosynthesis A_max of the most vigorous shoots (VC0) (7.34±0.55 μmol m⁻² s⁻¹) was significantly higher (P<0.001) than in shoots of other vigour classes (5.97±0.28 μmol m⁻² s⁻¹). Our data support the hypothesis that the changes in shoot and consequently crown architecture that are observed in ageing and declining trees can limit photosynthesis by reducing shoot hydraulic conductance. Abscission zones increase the hydraulic disadvantage of less vigorous compared to vigorously growing twigs. Cladoptosis might serve as a mechanism of selection between twigs of different efficiency.     

Stimulation by prostaglandin E2 of glucagon and insulin release from isolated rat pancreas

To ascertain whether prostaglandins (PG) may play a role in the secretion of glucagon and in an attempt to elucidate the conflicting observations on the effects of PG on insulin release, the isolated intact rat pancreas was perfused with solutions containing 1.1 × 10⁻⁹ to 1.8 × 10⁻⁵M PGE₂. In the presence of 5.6 mM glucose significant increments in portal venous effluent levels of glucagon and insulin were observed in response to minimal concentrations of 2.8 × 10⁻⁸ and 1.4 × 10⁻⁷M PGE₂, respectively; a dose-response relationship was evident for both hormones at higher concentrations of PGE₂. When administered over 60 seconds, 1.4^−10−6M PGE₂ resulted in a significant increase in glucagon levels within 24 seconds and in insulin within 48 seconds. Ten-minute perfusions of 1.4 × 10⁻⁶M PGE₂ elicited biphasic release of both islet hormones; Phase I glucagon release preceded that of insulin. Both phases of the biphasic glucagon and insulin release which occurred in response to 15-minute perfusions of 10 mM arginine were augmented by PGE₂. These observations indicate that PGE₂ can evoke glucagon and insulin release at concentrations close to those observed by others in the extracts of rat pancreas. We conclude that PG may be involved in the regulation of secretion of glucagon and insulin and may mediate and/or modify the pancreatic islet hormone response to other secretagogues.     

The effects of a 5-lipoxygenase inhibitor, AA-861, on PGI2-like substance production in guinea-pig lungs

To determine the effects of AA-861 on PGI₂ production in guinea-pig lungs, 3 g of guinea-pig lung was chopped in 4 ml of buffer (control group), in buffer with 4 μg/ml indomethacin (indomethacin group) and in buffer with 2.5 × 10⁻⁵M AA-861 (AA-861 group). The chopped lungs were incubated for 30 min. 250 μl of incubation medium from each group was assessed before and after 3, 5, 10, 15, 20, 25 and 30 min of incubation. The incubation medium was centrifuged and the supernatant was tested for a PGI₂-like substance (PGI₂) by platelet aggregation inhibition. PGI₂ was produced mainly during the initial 3–5 min of incubation and was decreased thereafter. PGI₂ production was almost completely inhibited in the indomethacin group at all of the incubation times and was partially inhibited in the AA-861 group during the initial 3–5 minutes. Endogenous 5-lipoxygenase products generated in the early stages of incubation seem to be involved in PGI₂ production in guinea-pig lungs.     

Role of prostacyclin on steroidogenesis by frog interrenal gland

The role of prostacyclin (PGI₂) on amphibian adrenal steroidogenesis was studied in perifused interrenal fragments from adult male frogs. Exogenous PGI₂ (3×10⁻⁸ M to 3×10⁻⁵ M) and, in a lesser extent, 6-keto-PGF_1α increased both corticosterone and aldosterone production in a dose-related manner. Short pulses (20 min) of 0.88 μM PGI₂ administered at 90 min intervals within the same experiment did not induce any desensitization phenomenon. A prolonged administration (6 h) of PGI₂ gave rise to an important increase in steroid production followed by a decline of corticosteroidogenesis. Indomethacin (IDM, 5 μM) induced a marked reduction of the spontaneous secretion of corticosteroid which confirmed the involvement of endogenous PGs in the process of corticosteroid biosynthesis. The IDM-induced blockade of corticosterone and aldosterone secretion was totally reversed by administration of exogenous PGI₂ in our model. Angiotensin II (AII) induced a massive release of 6-keto-PGF_1α, the stable metabolite of PGI₂. The increase of 6-keto-PGF_1α preceded the stimulation of corticosterone and aldosterone secretions. In contrast, the administration of ACTH did not modify the release of 6-keto-PGF_1α. These results indicate that PGI₂ might be an important mediator of adrenal steroidogenesis in frog. They confirm that the corticosteroidogenic actions of ACTH and AII are mediated by different mechanisms.     

Effects of indomethacin and PGE1 on the vasoconstrictor responses of the rabbit ear artery to nerve stimulation

Actions of PGE₁ and indomethacin on electrically induced vasoconstriction in isolated ear arteries of rabbits were studied. PGE₁ (8.5 × 10⁻⁹ M) reduced the vasoconstriction; this inhibition was inversely related to the rate of stimulation. Indomethacin (1.5 × 10⁻⁶ M) potentiated the constrictor responses to nerve stimulation. The degree of this potentiation was also frequency-dependent being greater at low (1 – 2 Hz) than at high (8 – 16 Hz) rate of stimulation. These findings support the view that prostaglandins, in addition to their action on vascular smooth muscle cells, play a functional role in the regulation of tone of the rabbit ear artery by a negative feed-back control of adrenergic neurotransmission.